The progression from adenomatous polyps to carcinoma is hypothesized to involve the interaction of genetic and environmental factors, thus metabolic pathways that process dietary carcinogens may influence the risk of developing cancer. The N-acetyltransferases, NAT1 and NAT2, are genetically polymorphic enzymes involved in these pathways and certain NAT* genotypes produce a rapid acetylator phenotype implicated in colon cancer risk. These polymorphisms have not been studied in a genetically defined group of individuals, which is essential to controlling for the influence of environmental factors. We hypothesize that there is an association between NAT phenotype and colon polyp susceptibility, which is more likely to be found between siblings than between unrelated individuals. We will test if NAT1* and NAT2* are susceptibility genes for colon polyps by genotyping sibling pars concordant and discordant for colon polyps, and by testing polymorphic markers in the NAT* region in concordant sib pairs to determine if this region is associated with polyp development. DNA from 100 sibling pairs concordant or discordant for polyps will be genotyped, and concordant sib pair analysis will be used to score NAT* alleles for identity-by-state that exceeds statistically expected numbers. Haplotypes will be generated using flanking markers to the NAT* region of chromosome 8p and correlated to phenotype. Certain haplotypes may be associated with increased susceptibility for colon polyps and, hence, their inheritance with increased risk. The identification of genes associated with colon polyp susceptibility will be clinically relevant because individuals who harbor high-risk polymorphisms can be identified and effective strategies for reducing colon cancer mortality can be developed.
